No abstract

Background: Current evidence suggests an important role of the interleukin-6 (IL-6) pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cytokine release storm in severely ill coronavirus disease 2019 (COVID-19) patients. Inhibition of the IL-6 pathway with tocilizumab has been employed successfully in some of these patients but the data is mostly consistent of case reports and series. Methods: We performed a systematic search of PubMed, Embase, and Medline from 22nd April 2020 and again on 27th April 2020 using the following search terms alone or in combination: "COVID-19," "coronavirus," "SARS-CoV-2," "COVID," "antiinterleukin-6 receptor antibodies," "anti-IL-6," "tocilizumab," "sarilumab," "siltuximab." We included studies that reported individual patient data. We extracted and analyzed individual level data on baseline characteristics, laboratory findings, and clinical outcomes. The primary endpoint was in-hospital mortality. Secondary endpoints included in-hospital complications, recovery rates, effect of patient characteristics on the primary outcome and changes in levels of inflammatory markers. Results: Three hundred fifty-two records were identified through a systematic search, of which 10 studies met the inclusion criteria. A single study currently under review was also added. Eleven observational studies encompassing 29 patients were included in the present review. There were more males (24 [82.8%]), and hypertension was the most common comorbidity (16 [48.3%]). Over an average of 5.4 hospital days, the primary endpoint occurred in 6 (20.7%) patients. Among surviving patients, about 10% had worsened disease and 17% recovered. The most common complication was acute respiratory distress syndrome (8 [27.6%]). The IL-6 level was significantly higher after the initiation of tocilizumab with median (interquartile range) of 376.6 (148-900.6) pg/mL compared to the baseline of 71.1 (31.9-122.8) pg/ mL (P = .002). Mean (standard deviation) levels of C-reactive protein (CRP) were significantly decreased following treatment 24.6 (26.9) mg/L compared to baseline 140.4 (77) mg/L (P < .0001). Baseline demographics were not significantly different among survivors and nonsurvivors by Fisher's exact test. Conclusion: In COVID-19 patients treated with tocilizumab, IL-6 levels are significantly elevated, which are supportive of cytokine storm. Following initiation of tocilizumab, there is elevation in the IL-6 levels and CRP levels dramatically

Prostate Dynamic-Contrast-Enhanced (DCE) MRI often exhibits fast and extensive global contrast reagent (CR) extravasation -measured by K trans , a pharmacokinetic parameter proportional to its rate. This implies that the CR concentration ( [CR]) is high in the extracellular, extravascular space (EES) during a large portion of the DCE-MRI study. Since [CR] is detected indirectly, through water proton signal change, the effects of equilibrium transcytolemmal water exchange may be significant in the data and thus should be admitted in DCE-MRI pharmacokinetic modeling. The implications for parameter values were investigated through simulations, and analyses of actual prostate data, with different models. Model parameter correlation and precision were also explored. A near-optimal version of the exchange-sensitized model was found. Our results indicate that ΔK trans (the K trans difference returned by this version and a model assuming exchange to be effectively infinitely fast) may be a very useful biomarker for discriminating malignant from benign prostate tissue. Using an exchange-sensitized model, we find that the mean intracellular water lifetime (τ i ) -an exchange measure -can be meaningfully mapped for the prostate. Our results show prostate glandular zone differences in τ i values.

The feasibility of Shutter-Speed Model (SSM) (Dynamic-Contrast-Enhanced) DCE-MRI pharmacokinetic analyses for prostate cancer detection was investigated in a pre-biopsy patient cohort. Differences of results from the fast exchange regime-allowed (FXR-a) SSM version and the fast-exchange-limit-constrained (FXL-c) standard model (SM) are demonstrated. Though the spatial information is more limited, post-DCE-MRI biopsy specimens were also examined. The MRI results were correlated with the biopsy pathology findings. Of all the model parameters, ROI-averaged K trans difference [ΔK trans ≡ K trans (FXR-a) − K trans (FXL-c)] or 2D K trans (FXR-a) vs. k ep (FXR-a) values were found to provide the most useful biomarkers for malignant/benign prostate tissue discrimination [at 100% sensitivity for a population of 13, the specificity is 88%] and disease burden determination. [The best specificity for the FXL-c analysis is 67%, with the 2D plot.] K trans and k ep are each measures of passive trans-capillary contrast reagent transfer rate constants. Parameter value increases with shutter-speed model (relative to standard model) analysis are larger in malignant foci than in normal appearing glandular tissue. Pathology analyses verify the SSM(FXR-a) promise for prostate cancer detection. Parametric mapping may further improve pharmacokinetic biomarker performance.